Certain ergot peptide alkaloids administered to the nasal mucosa

ABSTRACT

The present invention provides a nasal pharmaceutical composition comprising as active agent a compound of formula I, ##STR1## wherein R 1  is hydrogen or halogen, 
     R 2  is hydrogen or alkyl of 1 to 4 carbon atoms, 
     either (i) R 3  is isopropyl, sec-butyl, or isobutyl, R 4  methyl, ethyl or isopropyl and R 5  hydrogen and R 6  is hydrogen or methoxy or R 5  and R 6  are together a single bond, 
     or (ii) R 3  is benzyl, R 4  is methyl, R 5  is hydrogen and R 6  is hydrogen or methoxy, 
     in association with a pharmaceutically acceptable carrier or diluent, adapted for nasal or pulmonary administration.

This is a division of application Ser. No. 612,137, filed May 21, 1984now abandoned, which in turn is a division of application Ser. No.328,680, filed Dec. 8, 1981, now U.S. Pat. No. 4,462,983, which in turnis a continuation of application Ser. No. 194,998, filed Oct. 8, 1980,now abandoned, which in turn is a continuation of application Ser. No.33,242, filed Apr. 25, 1979, now abandoned, which in turn is acontinuation of application Ser. No. 852,775, filed Nov. 18, 1977, nowabandoned.

This invention relates to ergot peptide alkaloids.

The present invention provides a nasal pharmaceutical compositioncomprising as active agent a compound of formula I, ##STR2## wherein R₁is hydrogen or halogen,

R₂ is hydrogen or alkyl of 1 to 4 carbon atoms,

either (i) R₃ is isopropyl, sec-butyl, or isobutyl, R₄ methyl, ethyl orisopropyl and R₅ is hydrogen and R₆ is hydrogen and methoxy or R₅ and R₆are together a single bond,

or (ii) R₃ is benzyl, R₄ is methyl, R₅ is hydrogen and R₆ is hydrogen ormethoxy,

in association with a pharmaceutically acceptable carrier or diluent,adapted for nasal administration.

Satisfactory formulations may be formed in conventional manner. Theexact formulation will naturally depend on inter alia the active agentused, and the carrier or diluent used. Nasal compositions comprise anaqueous solution, conveniently containing a viscosity-increasing agentsuch as methyl cellulose. Such liquid compositions may be in an atomiseror a container adapted to provide drops. The compounds may be in solidform and have a particle size of up to 10 microns in diameter,preferably 0.5 to 5 microns. The carrier or diluent may be lactose,which may comprise 87.5 to 97.5% of the total weight, in a hard capsule,via an insufflator, e.g. for nasal administration.

The composition may be in the presence of a pharmaceutically acceptablepropellant such as a halogenated hydrocarbon and may be in a closedcontainer under pressure. The container may be adapted to deliver adiscrete dosage, e.g. from 0.1 to 5 mg of the compound. The containermay be an aerosol.

The present invention also provides a nasal applicator containing asactive agent a compound of formula I.

The applicator may be any conventional applicator for administering anactive agent to the nose. Generally, a dry or liquid spray is producedby such an applicator, which may, for example, be:

(a) an aerosol

(b) a liquid spray device or drop device for nasal administration, or

(c) a powder spray device

The applicator may be adapted to provide a unit dosage of the activeagent.

Various forms of applicators and compositions therefor will now bediscussed.

(1) Any aerosol device which produces a spray may be used, e.g. anebulizer. For example, spraying by means of ultrasonic aerosolappliances or by means of propellant gas pressure bottles is preferred.In this instance, the active agents are conveniently present in the formof solutions or suspensions.

If an ultrasonic aerosol appliance is used, the active agent isconveniently present as a solution. These solutions may be obtained bydissolving the active agent in a mixture of ethanol and water andconveniently adding to the resulting solution isotonizing additives,such as sodium chloride, and buffer substances, such as acetate buffer.The amount of active agent ranges conveniently from 0.1 mg to 5 mg/ml.The water/ethanol mixture used as solvent contains conveniently waterand ethanol as a ratio of from 98:2 and 80:20, preferably 90:10, (byvolume) respectively. Other additives used in order to obtain isotoniaand buffering substances should be present at an amount totalling 1% orless by weight relative to the total solution. Furthermore, it ispossible to add stabilizers, such as sodium pyrosulfite, ascorbic acid,etc., as well as flavouring substances, e.g. menthol, also at amounts ofat most 1% by weight related to the total solution.

If the active agent is to be sprayed by means of propellant gas pressurebottles, it is possible to use the solutions described for the use inultrasonic aerosol appliances. These solutions may be added tocompressed propellant gases, for example, fluorinated and/or chlorinatedhydrocarbons, e.g. trichlorofluoromethane (Frigen 11),dichlorodifluoromethane (Frigen 12), trichlorotrifluoroethane (Frigen113) or dichlorotetrafluoroethane (Frigen 114).

In place of the solutions in propellant gas pressure bottles,suspensions of the micronized active agent in the compressed propellantmay be used. In this case, it is convenient to add a tenside, forexample, Tween 80, or polyethyleneglycol esters of fatty acids,especially sorbitane monooleate, etc. The amount of active agent may be1 to 10% by weight and the amount of tenside 0.1 to 1% by weight relatedto the total amount of the suspension, including the propellant.

(2) To produce a nasal spray or nasal drops, the composition maycomprise the active agent in water, buffering substances, e.g. acetatebuffer, isotonizing additives, e.g. sodium chloride, preservatives, e.g.Nipakombin, solution aids, e.g. polyethylene glycol 400,viscosity-increasing agents, e.g. methyl cellulose, etc. The solutionsmay be in an atomiser, a spray appliance, or a nasal pipette. The amountof weight of the active agent in these solutions should be 1 to 10% byweight, and of the other additives, approximately 0.1 to 1% by weightrelated to the total amount of the solution. Instead of a solution,emulsions of the active agents in mono- and/or polyvalent alcohols, forexample triethylene glycol/ethanol, polyethylene glycol 300-400/ethanol,propylene glycol/ethanol, but also in a mixture of water and mono-and/or polyvalent alcohols, e.g. water/ethanol, water/polyethyleneglycol 300-400 may be used. The preferred amounts of the individualcomponents in the solvent mixture are described in Example 3. In thelatter, the active agent should be present at an amount of 0.5 to 5% byweight related to the total amount. Furthermore, oils such as sesameoil, paraffin oil, etc., in order to obtain the organic phase as well astensides (emulsifying agents), e.g. sorbitane monooleate, totalling upto 1% by weight, may be present during the production of emulsions.

The emulsion is conveniently administered by means of atomisers, plasticbottles each equipped with a nozzle or, after adding propellant gas, inpressure packs, the active agent in solution forming an emulsion withthe liquified propellant gas upon the addition of the liquified gas.

(3) For a nasal powder spray, the active agent may be present inmicronised from, e.g. of particle diameter less than 10 microns, e.g. 2to 10 microns, mixed together with micronised and non-micronisedlactose. The weight ratio of the active agent to the lactose may be0.25:12.5% to 99.75:87.5%. The mixture may be filled into hard gelatinecapsules (fill weight 20-40 mg per capsule) and sprayed in conventionalmanner, for example by means of a suitable insufflator.

The present invention also provides a method for treating an animal witha compound of formula I defined above which comprises administeringlocally the compound to the nasal mucous membranes.

In formula I, if R₂ signifies an alkyl group, this may especially bemethyl or isopropyl. If R₁ signifies halogen, this signifies fluorine,chlorine, bromine or iodine, especially bromine.

Preferred representatives of the compounds of formula I aredihydroergocristine, α- or β-dihydroergocryptine, dihydroergocornine,which are preferably used in the form of a mixture known asdihydroergotoxin, bromocriptine, dihydroergotamine and dihydroergonine.The compounds of formula I may be used in the free base form or in acidaddition salt forms, for example the methanesulphonate, maleate ortartrate.

It has been found that the nasal compositions, when administered locallyto the mucous membranes in the nose or the lungs inphencyclidine-anaesthetised rhesus monkeys, lead to a notable peak bloodconcentration of the compounds and/or a short onset time to peak bloodconcentration of the compounds on administration of, for example, 1 to10 mg of the compound. The concentration of the compound in the bloodmay be measured by conventional radioimmunoassay, e.g. according to theprinciples of J. Rosenthaler and H. Munzer, Experientia 32, 234 (1976).

For this administration, the dosage will, of course, vary depending onthe compound employed, mode of administration and treatment desired.However, in general, satisfactory results are obtained when administeredat a daily dosage of from about 0.001 to about 0.1 mg per kg animal bodyweight, conveniently given in divided doses 2 to 5 times a day or insustained release form. For the larger mammals, the total daily dosageis in the range from about 0.1 to about 10 mg.

The present invention therefore provides a method of treating animalswith a compound of formula I, as defined above, which comprisesadministering a therapeutically effective amount of a compond of formulaI for local administration to the nasal membranes of an animal in needof such treatment.

In the following Examples, all percentages, unless otherwise indicated,refer to parts by weight. Nipakombin means a 67:33 mixture ofp-hydroxybenzoyl methyl ester and p-hydroxybenzoyl propyl ester. Tween80 is polyethylene (20) sorbitan monooleate (I.C.I. England). Frigen 113is trichlorotrifluoroethane. Frigen 11/12/114 is a 25:50:25 (by volume)mixture of trichlorofluoromethane, dichlorodifluoromethane anddichlorotetrafluoroethane.

EXAMPLE 1 Dihydroergotamine Solution Aerosol

Basic Composition

    ______________________________________                                        Dihydroergotamine methanesulphonate                                                                   25 mg                                                 Ethanol (94%)          520 mg                                                 Water (distilled)      120 mg                                                 Frigen 11/12/114       1000 mg                                                ______________________________________                                    

Production

The dihydroergotamine, ethanol and water are mixed to give a solution.The solution is filled into an aerosol bottle. A valve outlet is fittedand crimped to seal the bottle. The required amount of propellant isadded through the valve.

EXAMPLE 2 Dihydroergotamine Suspension Aerosol

Basic Composition

    ______________________________________                                        Dihydroergotamine methanesulphonate                                                                         200    mg                                       micronised particle diameter <10μ                                          Tenside:                                                                      Sorbitan monooleate or Soya bean lecithin                                                                   20     mg                                        Frigen 113                                                                                                 to 1   ml                                       Frigen 11/12/114                                                              ______________________________________                                    

Production

The dihydroergotamine is triturated with the tenside in the presence ofa little Frigen 113 in a cooled mortar. Further Frigen 113 is added togive a homogenous mixture, if necessary using a polytron. The mixture isfilled into aerosol bottles while stirring and cooling continuously. Avalve outlet is fitted and crimped to seal the bottle. The requiredamount of propellant gas is then added through the valve.

EXAMPLE 3 Dihydroergotamine 2-Phase Aerosol Emulsion

Basic Composition

    ______________________________________                                        Dihydroergotamine methanesulphonate                                                                       50 mg                                             Sorbitan monooleate         5 mg                                              Ethanol (absolute)         100 mg                                             Glycol such as Triethylene glycol, propylene                                                              1 ml                                              glycol, Polyethylene glycol (MW 300-400)                                      Frigen 11/12/114           q.s.                                               ______________________________________                                    

If desired, the glycol may be replaced by ca. 200-300 mg water.

Production

Analogous to Example 1.

EXAMPLE 4 Dihydroergotamine Nasal Liquid Spray Applicator

Basic Composition

    ______________________________________                                                   4A     4B       4C       4D                                        ______________________________________                                        Dihydroergotamine                                                                          1.85%    1.85%    1.85%  1.85%                                   methanesulphonate                                                             Nipakombin   0.08%    0.08%    0.08%  --                                      Sodium acetate                                                                              0.168%   0.168%   0.168%                                                                               0.168%                                 trihydrate                                                                    Glacial acetic acid                                                                        0.42%    0.42%    0.42%  0.42%                                   Methyl cellulose                                                                           --       0.5%     0.5%   1.0%                                    Polyethylene --       --       10%    10%                                     glycol 400                                                                    Tween 80     --       --       --     0.1%                                    Chlorohexidine                                                                             --       --       --     0.01%                                   diacetate                                                                     Ethanol (94%)                                                                              15%      15%      15%    15%                                     Water        to 100%  to 100%  to 100%                                                                              to 100%                                 ______________________________________                                    

Production

The ingredients without the dihydroergotamine and with some of the waterare mixed together. The dihydroergotamine is then added, and the mixturecompleted by addition of water. The resulting solution may be madeisotonic, if desired, by the addition of sodium chloride, mannitol orsorbitol, etc., and is filled into a nasal spray applicator, e.g. anatomiser.

EXAMPLE 5 Dihydroergotamine Powder Spray Applicator

A mixture of micronised dihydroergotamine methanesulphonate with lactoseis filled into a gelatine capsule.

For nasal application, the contents are administered by spraying intothe nostril by means of a rubber bulb or other atomiser.

EXAMPLE 6 Bromocriptine Suspension Aerosol

Basic Composition

    ______________________________________                                                              Wt. per dose                                            ______________________________________                                        Bromocriptine methanesulphonate                                                                       1.324   mg                                            Soya bean lecithin      0.2     mg                                            Absolute ethanol        3       mg                                            Frigen 113              13.5    mg                                            Frigen 11/12/114        47.50   mg                                            ______________________________________                                    

Production

A composition containing 90 such doses is prepared in analogous mannerto that described in Example 2.

EXAMPLE 7 Bromocriptine Nasal Liquid Spray

Basic Composition

    ______________________________________                                                    7A       7B        7C                                                         mg       mg        mg                                             ______________________________________                                        Bromocriptine methane-                                                                      8.63       8.63      2.87                                       sulphonate                                                                    Ascorbic acid 0.50       0.5       --                                         Glacial acetic acid                                                                         to pH 2.9  to pH 2.9 1.55                                       Sodium acetate                                                                              --         --        1.02                                       Mannitol      50         50        45                                         Methyl cellulose                                                                            --         10        --                                         Ethanol (94%) 120        120       --                                         Water         to 1.00 ml to 1.00 ml                                                                              to 1.00 ml                                 ______________________________________                                    

Production

A 14 ml bottle fitted with a piston spray device is filled with theabove composition in a CO₂ atmosphere.

Compositions may be made using dihydroergonine or dihydroergotoxin inappropriate amounts instead of dihydroergotamine in Examples 1 to 5 orbromocriptine in Examples 6 and 7.

What is claimed is:
 1. A pharmaceutically acceptable nasal sprayapplicator consisting essentially of a nasal applicator containingtherein an ergot peptide alkaloid composition for nasal administrationcomprising per unit dose a therapeutically effective amount ofdihydroergocristine or an ergot peptide alkaloid of the formula ##STR3##wherein R₁ is hydrogen or halogen,R₂ is hydrogen, methyl or isopropyl,and either (i) R₃ is isopropyl, sec-butyl or isobutyl, R₄ is methyl,ethyl or isopropyl, and R₅ is hydrogen and R₆ is hydrogen and methoxy orR₅ and R₆ are together a single bond, or (ii) R₃ is benzyl, R₄ ismethyl, R₅ is hydrogen and R₆ is hydrogen or methoxy,or apharmaceutically acceptable acid addition salt thereof, in associationwith a pharmaceutically acceptable carrier suitable for nasal sprayadministration, said nasal applicator being adapted to administer a unitdose of the ergot peptide alkaloid to the mucous membrane of the nose.2. A pharmaceutically acceptable nasal spray applicator as claimed inclaim 1 wherein the composition comprises per unit dose 0.1 to 5 mg ofthe ergot peptide alkaloid.
 3. The nasal spray applicator as claimed inclaim 1 wherein the compound of formula I is dihydroergotamine.
 4. Thenasal spray applicator as claimed in claim 1 wherein the compound offormula I is bromocriptine.
 5. The nasal spray applicator as claimed inclaim 1 wherein the compound of formula I is dihydroergotoxine.
 6. Thenasal spray applicator as claimed in claim 1 adapted to administer 0.1to 5 mg of the ergot peptide alkaloid per administration.
 7. A nasalspray applicator according to claim 1 in which the ergot peptidealkaloid composition is in liquid form.
 8. The nasal spray applicator asclaimed in claim 7 wherein the ergot alkaloid composition contains 0.1to 5 mg of active agent per ml of solution.
 9. A nasal spray applicatoraccording to claim 7 in which the ergot peptide alkaloid compositioncontains a propellant acceptable in nasal administration.
 10. A nasalspray applicator according to claim 9 in which the propellant is ahalogenated hydrocarbon.
 11. A nasal spray applicator according to claim7 in which the ergot peptide alkaloid composition is in the form of anaqueous solution containing a viscosity increasing agent.
 12. A nasalspray applicator according to claim 11 in which the viscosity increasingagent is methyl cellulose.
 13. A nasal spray applicator according toclaim 7 in which the carrier is a non-aqueous solvent.